TY - JOUR
T1 - Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes
AU - Assary, Elham
AU - Coleman, Jonathan R.I.
AU - Hemani, Gibran
AU - van de Weijer, Margot P.
AU - Howe, Laurence J.
AU - Palviainen, Teemu
AU - Grasby, Katrina L.
AU - Ahlskog, Rafael
AU - Nygaard, Marianne
AU - Cheesman, Rosa
AU - Lim, Kai
AU - Reynolds, Chandra A.
AU - Ordoñana, Juan R.
AU - Colodro-Conde, Lucia
AU - Gordon, Scott
AU - Madrid-Valero, Juan J.
AU - Thalamuthu, Anbupalam
AU - Hottenga, Jouke-Jan
AU - Mengel-From, Jonas
AU - Armstrong, Nicola J.
AU - Sachdev, Perminder S.
AU - Lee, Teresa
AU - Brodaty, Henry
AU - Trollor, Julian N.
AU - Wright, Margaret
AU - Ames, David
AU - Catts, Vibeke S.
AU - Latvala, Antti
AU - The Within Family Consortium
AU - Walters, Robin G.
AU - Morris, Sam
AU - Chen, Zhengming
AU - Lin, Kuang
AU - Hughes, Amanda M.
AU - Millwood, Iona Y.
AU - Li, Liming
AU - Havdahl, Alexandra
AU - Pingault, Jean Baptiste
AU - Hill, W. David
AU - Boivin, Michel
AU - Benjamin, Daniel J.
AU - Keller, Matthew C.
AU - Torvik, Fartein A.
AU - Li, Shuai
AU - de Geus, Eco
AU - Huider, Floris
AU - Akingbuwa, Wonu
AU - Ask, Helga
AU - Magnus, Per
AU - Åsvold, Bjørn Olav
AU - Brescianini, Sonia
AU - Giannelis, Alexandros
AU - Willoughby, Emily A.
AU - Sung, Joohon
AU - Lee, Soo Ji
AU - Pyun, Hyojin
AU - Evans, David
AU - Archie, Campbell
AU - Vuoksimaa, Eero
AU - Mallard, Travis
AU - Paige Harden, K.
AU - Tucker-Drob, Elliot M.
AU - Oskarsson, Sven
AU - Hammond, Christopher J.
AU - Christensen, Kaare
AU - Taylor, Mark
AU - Lundström, Sebastian
AU - Larsson, Henrik
AU - Karlsson, Robert
AU - Pedersen, Nancy L.
AU - Mather, Karen A.
AU - Medland, Sarah E.
AU - Boomsma, Dorret I.
AU - Martin, Nicholas G.
AU - Plomin, Robert
AU - Bartels, Meike
AU - Lichtenstein, Paul
AU - Kaprio, Jaakko
AU - Eley, Thalia C.
AU - Davies, Neil M.
AU - Munroe, Patricia B.
AU - Keers, Robert
N1 - R. Keers and E.A. were involved in conceptualizing and designing the study. R. Keers acquired funding. L.J.H., E.A., R. Keers, G.H., N.M.D. and J.K. developed the analysis pipeline. E.A., R. Keers., L.J.H., T.P., J.K. and N.M.D. were involved in data acquisition and collation. E.A. project managed and performed data analyses. J.R.I.C. and P.B.M. played a key role in supervising the analyses and P.B.M. oversaw the progress. G.H. performed simulation and Mendelian randomization analyses. E.A. wrote the first draft. E.A., J.R.I.C., P.B.M., G.H., N.M.D., J.K. and T.C.E. played a key role in interpreting the results and revising the manuscript. For the Danish Twin Registry, M.N. performed the data analysis, K.C. was the principal investigator and J.M.-F. collected and prepared the data. For the Finnish Twin Cohort, T.P. performed the data analysis, J.K. was the principal investigator and E.V. and A.L. collected and prepared the data. For the Murcia Twin Registry, J.J.M.-V. and L.C.-C. performed the data analysis and J.R.O. was the principal investigator. For The Netherlands Twin Register, M.P.v.d.W. and J.-J.H. performed the data analysis and M.B. and D.I.B. were the principal investigators. For the OATS, A.T. and N.J.A. performed the data analysis, P. Sachdev, T.L., H.B., J.N.T., M.W. and D.A. were the principal investigators and V.S.C. and K.A.M. collected and prepared the data. For the QIMR studies, K.L.G. performed the data analysis, N. M. and S.M. were the principal investigators and S. Gordon collected and prepared the data. For the Swedish Twin Registry’s ageing study, C.A.R. performed the data analysis and N.L.P. was the principal investigator. For the Swedish Twin Registry’s Child and Adolescent Twin Study in Sweden, E.A. performed the data analysis, P.L. was the principal investigator and R.K., M.T., S.L. and H.L. collected and prepared the data. For the Swedish Twin Registry’s PSYCH, TwinGene and Young Adult Twin Study in Sweden studies, R.A. performed the analysis and S.O. was the principal investigator. For the Twins Early Development Study, R.C. and E.A. performed the data analysis, T.C.E. and R.P. were the principal investigators and K.L. prepared the data. For TwinsUK, E.A. performed the data analysis and C.J.H. prepared the data. All authors contributed to writing and critically reviewing the manuscript.
PY - 2025/8
Y1 - 2025/8
N2 - Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods. We combined data from 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct one of the largest genome-wide association study meta-analyses of monozygotic phenotypic differences, in children, adolescents and adults separately, for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism and wellbeing. The proportions of phenotypic variance explained by single-nucleotide polymorphisms in these phenotypes were estimated (h2 = 0–18%), but were imprecise. We identified 13 genome-wide significant associations (single-nucleotide polymorphisms, genes and gene sets), including genes related to stress reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. This is the largest genetic study of monozygotic twins to date by an order of magnitude, evidencing an alternative method to study the genetic architecture of environmental sensitivity. The statistical power was limited for some analyses, calling for better-powered future studies.
AB - Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods. We combined data from 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct one of the largest genome-wide association study meta-analyses of monozygotic phenotypic differences, in children, adolescents and adults separately, for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism and wellbeing. The proportions of phenotypic variance explained by single-nucleotide polymorphisms in these phenotypes were estimated (h2 = 0–18%), but were imprecise. We identified 13 genome-wide significant associations (single-nucleotide polymorphisms, genes and gene sets), including genes related to stress reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. This is the largest genetic study of monozygotic twins to date by an order of magnitude, evidencing an alternative method to study the genetic architecture of environmental sensitivity. The statistical power was limited for some analyses, calling for better-powered future studies.
UR - https://github.com/Elham-Assary/MZ-differences-GWAS
U2 - 10.1038/s41562-025-02193-7
DO - 10.1038/s41562-025-02193-7
M3 - Article
C2 - 40494901
AN - SCOPUS:105007678976
SN - 2397-3374
VL - 9
SP - 1683
EP - 1696
JO - Nature Human Behaviour
JF - Nature Human Behaviour
IS - 8
ER -